Aphallia - congenital absence of the penis: a systematic review

Background Aphallia is a rare congenital anomaly often associated with other urogenital anomalies. The management of aphallia cases for both the immediate and long-term treatment of patients with aphallia pose a major dilemma. Patients are at risk for psychosocial and psychosexual challenges throughout life. Methods A systematic review was conducted on aphallia cases. We searched online databases until March 2023 for relevant articles and performed according to the PRISMA-P guidelines. Results Of the 43 articles screened, there were 33 articles included. A total of 41 patients were analyzed qualitatively. Asia is the region with the most aphallia cases with 53% (n:22), while the United States is the country with the most most reported aphallia cases 31% (n:13). Most cases were identified as male sex (n: 40), and most cases were neonate with 68% (n:28) cases. Physical examination generally found 85% (N = 35) with normal scrotal development and palpable testes. The most affected system with anomalies is the genitourinary system with fistulas in 80% (n:29) cases. Initial management in 39% (n:16) of patients involved vesicostomy. Further management of 31% (n:13) included phalloplasty or penile reconstruction, and 12% (n:5) chose female sex. 17% (n:7) of patients refused medical treatment or were lost to follow-up, and 12% (n = 5) patients deceased. Conclusion Aphallia is a rare condition and is often associated with other inherited genitourinary disorders. In most cases, physical examinations are normal except for the absence of a phallus, and laboratory testing shows normal results. The initial management typically involves the vesicostomy procedure. Subsequent management focuses on gender determination. Currently, male sex is preferred over female. Due to the significant variability, the rarity of cases, and the lack of long-term effect reporting in many studies on aphallia, further research is needed to minimize bias.

can also lead to proximal urethrorectal communication, which will explain the high incidence of concurrent anorectal anomalies seen in aphallia patients [2].
Both the immediate and long-term management of aphallia patients pose a major dilemma [1] Patients are at risk for psychosocial and psychosexual challenges throughout life [3].These patients require a multidisciplinary approach that often includes psychologists, endocrinologists, pediatric urologists, pediatric surgeons, plastic surgeons and social workers because not all community health care centers have access to every one of the specialties mentioned above [3].In this review we aim to address the variability of disease presentation, the associated anomalies of the disease and will review the current knowledge of the treatment options in all age patients of aphallia.

Search strategy
We included case reports/ series involving patients with aphallia.This review follows the guidelines in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Protocol (PRISMA-P) to increase comprehensiveness and transparency of reporting [4].We searched two electronic databases, Medline and Sciencedirect, until March 2023.The following keywords and medical subject headings were used: Aphallia, penile agenesis, absence of penile shaft, absence of penis, clitoral absence, absence of phallus, and absence of corpora cavernosa.

Study selection
The database search was conducted by two authors (P.Y. and E.T).Eligibility criteria for inclusion in the review was a specific focus on aphallia in all age of patients.Operation technique focus and non-English articles were excluded.
All articles reporting one or more cases of aphallia were obtained in full-text.Two authors (P.Y. and E.T) independently extracted data from all studies into data summary tables.The articles which fulfilled the eligibility criteria were included in this review.The following data were collected: age, clinical findings, supporting investigations, laboratory findings and management.The final selected papers were reviewed by three authors (P.E.Y., Y.Z., J.A.T.)

Data extraction and synthesis
The information that was extracted included the following: author and year of study; demographics of the patient, including age, proportion of males and female, weight and country, presenting signs and symptoms with percentage distribution; laboratory data and imaging findings with percentage distribution; and management with percentage distribution.Due to the qualitative, summative nature of this review and significant variations in participants, presentation, laboratory data, imaging and treatments, a meta-analysis could not be conducted and effect sizes could not be calculated.

Results
Our search resulted in 94 potentially relevant articles, of which 30 articles are duplicates.From the 64 articles identified, a total of 43 articles were screened for eligibility; and 33 articles met the full inclusion criteria (Fig. 1).
They included 41 patients with aphallia.The results of these 33 studies are summarized in Table 1.
• Abdominal and pelvis ultrasonography: Severe hydronephrosis and significant diminished left renal cortical thickness along with tough dilation and cystic pelvis were spotted.Mild to average hydronephrosis was seen in the right kidney with mild reduced cortical thickness and pelvis dilatation.
• The patient was discharged for penis reconstruction treatment plan • Urinary opening wasn't seen in perineum.
• Urine was mixed with meconium.• The urine passage was through the rectum by a urethrorectal fistula located in the rectum.• The ureters and bladder were normal.
• The neonate continued to have creatinine rise and glomerular filtration rate (GFR) decline • The scrotum was normal and the neonate had bilaterally descended testes.
• Severe renal failure in fifth day of admission.
• Anus was placed normally • The urethral opening was not visible anywhere in the perineum.• The hydronephrosis was managed with a vesicostomy to relieve ureteric obstruction.
• Presence of an abnormal common opening for urine and stool.
• Peritoneal dialysis for 48 h and given supportive care.
• Loose stools and severe dehydration.
• A urinary infection with Klebsiella species was found and treated with appropriate antibiotics • The stenosed perineal urethral orifice opened in the anterior wall of the anorectum.
• The urethral opening was separated from the anorectum and transposed at the penoscrotal junction as perineal urethrostomy.
• De Castro Phalloplasty with 4 × 5-cm lower abdominal quadrangular flap was performed with suprapubic cystostomy.• The anus was in normal position, permeable, with the presence of meconium mixed with urine.
• Karyotype chromosomes: 46,XY • At the age of 1 and a half years, the cosmetic aspect of the perineum was satisfactory with a wellanchored urethra at the level of the median raphe and the anus was at its normal position.• Digital rectal examination revealed the urethral meatus could be detected on the anterior wall of the rectum posterior to the sphincter with the depth of 1 cm.
• Voiding cystography: Oval-shaped urethra was observed between the coccygeal apex and the bladder in the lateral position.
• Testicular sperm extraction showed large number of progressive sperm in the fluid smear of the fistula using the perineal approach, the urethra was exposed and divided from the urethro-rectal junction.
• The urethra had an opening into the rectum about 2.5-3 cm distal to the bladder neck.
• The urethra was then dissected free from its underlying connective tissue up nearly to the bladder neck to establish a perineal urethrostomy • The urethral meatus was located at the base of the genital tubercle.
• Amplification by polymerase chain reaction of the 5a-reductase and the androgensbinding receptor were normal.
• The patient will require the creation of a functional vagina at puberty.
• There was a normally located anus.• Karyotype chromosomes: 46,XY • The patient underwent bilateral orchiopexy, followed by perineal transposition of urethra to avoid chronic urinary tract infection.
• The scrotum was normal with a median raphe.
• Voiding cystourethrogram via the rectal urethral opening: Showed a normal bladder • Chromatin negative buccal smear.
• Postoperatively, appropriate antibiotics were administered and the patient discharged without any complaints.
• There was a normally placed anus with an anterior skin tag.

Managements
• The urine exited from the anus, through the urethral meatus on the anterior rectal wall.
• Urinalysis and urine culture: Showed persistent infections of Escherichia coli and Pseudomonas • Globular mass suggestive of an ectopic hydronephrotic kidney was palpated on the right side of the abdomen.
32. M.C.Carr-1994 [32] Neonate, H-0, GA 35 weeks 2400 g Aphallia and cloaca exstrophy • Abnormalities on physical examination included an omphalocele, a meconium stained umbilical cord that was markedly ectatic, a bifid scrotum with palpable gonads and absent phallus separation of the pubic rami, and urethral or rectal openings on the perineum.
• • Bilateral orchiectomy, urethral transposition and labial construction with scrotal skin were performed.
• A skin tag and small proboscis were noted at the anterior anal verge.
• Cystogram: Demonstrated a normal bladder without evidence of fistulous communication with the rectum.
• Karyotype chromosomes: 46,XY • A small opening at the base of the skin tag was recognized as the urethral meatus.Admission serum creatinine was 1.2 mg./ dl.(normal 0.9 to 1.5) and mild hyperchloremic acidosis • A 5F feeding tube was inserted into the bladder and the serum creatinine decreased to 0.5 mg./dl.

Managements
• A small amount of erectile tissue was present anteriorly, which was engulfed by a normal scrotum.
• Diethylenetriaminepentaacetic acid renal scan with delayed images: Defined the hydronephrotic right kidney but no function was noted on the left side.Delayed images revealed nuclide in the retrovesical cystic mass • At 10 days after birth a dysplastic left kidney that drained into a midline cystic mass was resected.The mass communicated distally in the area of the prostatic urethra.
• Voiding cystourethrogram: visualized a trabeculated bladder with faint contrast medium in the dilated retrovesical mass and a type III posterior urethral valve.
• Vesicostomy was performed to provide unobstructed drainage of the right kidney • Bilateral scrotal orchiectomy then was performed.
• The scrotal halves were brought into the midline to simulate labia majora and the glans-like tubercle was left intact at the superior margin of the labial cleft • Patient underwent antegrade fulguration of the posterior urethral valve with closure of the vesicostomy.

Discussion
Penile agenesis is a very rare genitourinary occurrence with a prevalence of 1 in 30 million births [1].Aphallia is defined as the absence of a phallus and ectopic urethral opening and associated with well-developed scrotum and bilateral palpable testes [35].
In males, the absence of the penis is characterized by the absence of three penile components: two corpora cavernosa and the corpus spongiosum.Aphallia can also occur in female patients, although it is considered less common and more difficult to diagnose.This is most likely due to a high association with bladder agenesis and intrauterine fetal demise [35].
In this review, the country with the most reported cases of aphallia was the United State [2,7,8,12,16,30,[32][33][34], but regionally the most cases were in Asia.Patients with aphallia generally present at birth [2, 3, 8-12, 14, 17, 18, 21, 22, 25, 28, 30, 33], but in some cases patients come after being older than 1 month, for unknown reasons.All patients were male (1-3,7-29), except for one case where the clitoris was absent in a woman [2].Most of the previous reports of aphallia were limited to boys, with some reports of clitoral agenesis in girls.This may be related to the underdiagnoses of aphallia in girls, where the absent clitoris is far less conspicuous than an absent penis.
Physical examination in the majority of studies showed that most patients had normal scrotal growth [1-3, 5-19, 22-25, 27-31, 33, 34], normally descended testes [1-3,  [13,21,26,32], and undescended testes which occurred in a minority of cases for unknown reasons [8,24,25,31].This systematic review shows the various Imaging and laboratory modalities used with aphallia, and almost every case used a different modality.This may be because of the many anomalies that occurred, so it requires a different approach for each case and it should be noted that most cases have multiple anomalies.
The management of each case can be different because almost every case had different anomalies.Cystostomy was performed in most cases as the initial management of aphallia [7-11, 13, 16, 18, 20-22, 26, 27, 32, 33], especially those found to have a fistula, to allow draining of the urine, and to correct the fistula.
For advanced management, phalloplasty was more often done compared to patients who choose the female sex.Although aphallia is associated with congenital abnormalities, the mortality rate is quite low, and is caused by complications mainly due to sepsis and uricemia [13,21,25,31].
Aphallia management is divided into three distinct phases: acute, subacute, and chronic.Previously, aphallia patients needed to be checked for chromosomes to exclude other causes of sexual differentiation and abnormalities such as congenital adrenal hyperplasia or other penile abnormalities (severe hypospadias, epispadias, and hidden or micropenis) [35].
In the acute phase, therapy is supportive and involves managing life-threatening complications.Vesicostomy can be performed, especially in patients who present with sepsis or urinary tract obstruction due to the absence of the urethra, to drain the urinary tract, relieve pressure, and prevent infection.In aphallia, urine obstruction is not always present, as seen in the case of urethra-perineal fistula, and no urine transfer is required at this stage [35].Subacutely, perineal urethrostomy or catheterization vesicostomy can be performed for the separation of urethrorectal fistulas and in patients with a urethra that is too small or absent in order to gain access to the bladder [16].Additionally, a pseudophallus can be created to enable patients to identify themselves as male [16].
The gender determination of aphallia is still controversial.In the past, surgery was recommended as the only reconstructive option in these cases, known as feminization genitoplasty.This recommendation was based on the belief that raising these patients as males could be disruptive, and it was considered better to be an imperfect female than an inadequate male.The management strategy includes early bilateral orchidectomy to prevent postnatal androgen implantation, followed by vaginal interposition and hormonal therapy during puberty.However, these patients often experience high levels of gender dysphoria, due to prenatal androgen implantation [35].
Prenatal and early neonatal androgen imprinting has been studied in animal models, pregnant women undergoing hormone therapy, and children with congenital adrenal hyperplasia.It has been shown that fetal exposure to testosterone has an influence on childhood sex interests, such as playmates and activity preferences, as well as later sexual orientation, which tends towards typically male behaviors and gynecophilia [35].
Sex determination considerations should be based on the sex that provides the best prognosis in terms of reproductive function, the ability to function sexually, the appearance of the external genitalia, and the patient's self-identification with a particular sex.Therefore, although some authors still recommend feminizing genitoplasty for infants and newborns, it is now generally accepted that genetically normal males with aphallia should be supported surgically as males until the patient is old enough to identify their own sex, thus reducing gender dysphoria [35].
Chronic management is to create the functional prosthetic and aesthetic neophallus [16].Construction of a functional neophallus requires a multidisciplinary team approach.One of the most considered treatment options for long-term management is phalloplasty, which can be performed before the patient reaches puberty.The gold standard technique for phalloplasty is microsurgical phalloplasty with a radial forearm free flap, which has shown good results and positive outcomes in terms of patients' self-esteem and sexual well-being [36].
This study has several limitations.This review includes only studies published in English and may result in publication bias (language) in selecting studies due to the exclusion of other relevant articles published in languages other than English.Some articles lack data regarding patients, including age, clinical presentation, investigations, and evaluation of family history.This may be due to the rarity of cases and the variability of cases of aphallia, so that there is no standard method of aphallia.In addition, evaluating the progression of aphallia treatment is a challenge because many studies have not reported the long-term progress of the treatment chosen.Long-term follow-up is essential, but there is a distinct lack of information regarding the long-term outcomes of these patients.These patients need lifelong follow-up in a team of specialists, especially after puberty.

Conclusions
This systematic review shows that aphallia is a rare congenital anomaly, and all cases were associated with other genitourinary congenital abnormalities, especially fistulas between the genital tract and the rectum.Although often associated with other congenital abnormalities, most physical examinations and laboratory tests showed normal results except for the phallus.Initial management generally includes vesicostomy, and for advanced management, sex determination is recommended.Currently, male sex is preferred over female sex, possibly due to the predominance of male patients.

Fig. 1
Fig. 1 Prisma flow chart and a peculiar tuft of tissue at the anterior anal verge.• A renal and abdominal sonogram: Demonstrated a large retrovesical cystic mass with anterior bladder displacement.The right kidney and ureter were dilated but a left kidney could not be demonstrated.

Table 1
Study characteristics

Table 2
Characteristics of all patients

Table 3
Physical examination finding in all cases

Table 4
Laboratory examination in all cases

Table 5
Anomalies' finding in all cases

Table 6
Management summary in all cases